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Expression and Modulation of Potassium Channels in Neuroblastoma

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Expression and Modulation of Potassium Channels in Neuroblastoma Expression and modulation of potassium channels in neuroblastoma Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Master of Philosophy By Meraj Ondhia July 2017 Abstract Neuroblastoma is a paediatric cancer derived from the sympathoadrenal cell lineage. Most cases are diagnosed in children under the age of 5 and neuroblastoma is responsible for 15% of paediatric oncology deaths. Neuroblastoma tumours demonstrate remarkable clinical variability which reflects their significant biological heterogeneity. Currently, even with intensive multimodal treatment, patients with high-risk disease have a poor prognosis. Therefore, further understanding of the biology of neuroblastoma may contribute to developing novel therapeutic approaches. Potassium (K+) channels are involved in the regulation of many biological processes associated with cancer; including cell proliferation, apoptosis, migration and angiogenesis. Overexpression of multiple K+ channels has been demonstrated in a number of types of cancer. However, the role of K+ channels in neuroblastoma has yet to be extensively evaluated. In this study K+ channel gene expression was assessed initially in primary neuroblastoma tumours and in two high-risk, human neuroblastoma-derived cell lines: BE2C and SKNAS. Quantitative PCR, western blotting and immunocytochemistry were used to assess K+ channel expression in BE2C and SKNAS cells. KCNQ2/Kv7.2, a voltage-gated K+ channel, was found to be highly expressed in the BE2C cell line and expression of KCNQ2/Kv7.2 was 101 fold greater in BE2C cells relative to SKNAS cells. Furthermore, functional assays demonstrated that XE991, a compound which inhibits KCNQ/Kv7 channels, reduced BE2C cell proliferation in vitro. In addition, XE991 was found to induce morphological changes in BE2C cells, akin to neuronal differentiation, in vitro. The effect of XE991 on BE2C cell proliferation in vivo was investigated using the chick embryo model, however no significant effect was detected. We have established that K+ channels are expressed by neuroblastoma cells and differential expression exists between two neuroblastoma cell lines. KCNQ2 expression may contribute to the biological heterogeneity observed in neuroblastoma cell lines and primary tumours. Furthermore, it is evident that modulation of KCNQ2/Kv7.2 has a role in BE2C cell behaviour in vitro. ii Acknowledgements There are many people I would like to thank for their encouragement and support throughout the course of this project. I entered the laboratory not knowing how to hold a pipette correctly and less than one year and many experiments later I have learnt many valuable lessons both inside and outside the laboratory. So for this incredible opportunity my deepest gratitude goes to my supervisors Dr John Quayle, Dr Diana Moss and Professor Paul Losty. Dr Quayle and Dr Moss have been excellent at guiding me throughout this year and their advice and encouragement has been fundamental to this project. Thank you for affording me the opportunity to work in your laboratories and for being ever-willing to answer my questions. I would like also like to thank Professor Paul Losty who has provided excellent advice and support throughout the year. I must also thank Dr Tomoko Kamishima, her patient and excellent teaching style in the laboratory was pivotal for me to become confident with working in the laboratory independently. I am hugely grateful for the help and guidance I have received from Dr Rabiu Inuwa and Rasha Swadi. In the laboratory they have gone above and beyond to assist me from the very first day and in the office they have provided warm friendship throughout the year. I wish them both the very best for the future. I would like to thank Dr Mingming Yang for his help and friendship. I would also like to acknowledge Dr Chris Law for his help in conducting FACS. I would like to thank Alder Hey Children’s Hospital for providing the funding to undertake this unique and invaluable opportunity. Lastly and most importantly I would like to thank my parents and sister for their unconditional love and support. iii List of abbreviations A260 Absorbance at 260nm A280 Absorbance at 280nm AHSCT Autologous haematopoietic stem cell transplant ALK Anaplastic lymphoma kinase ASCL1 Achaete-scute homolog-1 ATP Adenosine triphosphate ATRX Alpha thalassemia/mental retardation syndrome X-linked BCA Bicinchoninic acid BMP Bone morphogenetic protein BSA Bovine serum albumin CAM Chorioallantoic membrane cDNA Complementary deoxyribonucleic acid CDK Cyclin dependent kinase CNS Central nervous system CO2 Carbon dioxide Cq Cycle quantification CT Computed tomography DAPI 4’, 6-Diamindino-2-Phenylindole,Dihydrochloride DiBAC4(3) Bis-(1,3-Dibutylbarbituric Acid) Trimethine Oxonol DMEM Dulbecco’s modified Eagle’s medium DMSO Dimethyl sulfoxide E Embryonic day EDTA Ethylenediaminetetraacetic acid FACS Fluorescence activated cell sorting FBS Fetal bovine serum GEMM Genetically engineered murine model GFP Green fluorescent protein hERG Human ether-a-go-go related gene HBSS Hanks balanced salt solution HPRT1 Hypoxanthine phosphoribosyltransferase 1 HRP Horseradish peroxidase HVA Homovanillic acid iv ICC Immunocytochemistry IDRF Image-defined risk factor IHC Immunohistochemistry INPC International Neuroblastoma Pathology Classification INRG International Neuroblastoma Risk Group INRGSS International Neuroblastoma Risk Group Staging System INSS International Neuroblastoma Staging System K+ Potassium ion K2P Two pore potassium channel KCa Calcium-activated potassium channel KCN Potassium channel Ki67 Antigen identified by monoclonal antibody Ki67 Kir Inward rectifying potassium channel KLF4 Kruppel-Like Factor Kv Voltage-gated potassium channel MDM2 Mouse double minute 2 homolog MIBG Metaiodobenzylguanidine MRI Magnetic resonance imaging mRNA Messenger ribonucleic acid MTT 3-(4,5- dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide MYC Myelocytomatosis viral related oncogene NB84 Uncharacterised antigen in neuroblastoma cells NCBI National Centre for Biotechnology Information NCC Neural crest cell NEAA Non-essential amino acids NRQ Normalised relative quantification NRT No reverse transcriptase control NSE Neuron-specific enolase NTC No template control PBS Phosphate buffered saline PFA Paraformaldehyde PHOX2A Paired-like homeobox 2A PHOX2B Paired-like homeobox 2B PNT Peripheral neuroblastic tumour v PSS Physiological saline solution qPCR Quantitative Polymerase Chain Reaction RG Reference gene ROBO2 Roundabout, axon guidance receptor, homologue 2 RQ Relative quantification RT Reverse transcriptase SDS Sodium dodecyl sulfate SEM Standard error of the mean SSC Sodium citrate buffer STMN4 Stathmin-like 4 TBST Tris-buffered saline with Tween 20 TG Target gene TrKA Tropomyosin receptor kinase A VMA Vanillylmandelic acid WB Western blotting XE-991 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone vi Table of contents Abstract ............................................................................................................................................ ii Acknowledgements .......................................................................................................................... iii List of abbreviations ......................................................................................................................... iv Table of contents..............................................................................................................................vii List of figures ................................................................................................................................... xiii List of tables .................................................................................................................................... xvi Chapter 1: Introduction ..................................................................................................................... 1 1.1 Neuroblastoma ............................................................................................................................ 2 1.1.2 Epidemiology, genetic predisposition and risk factors ........................................................... 2 1.1.3 The neural crest .................................................................................................................... 2 1.1.3.1 Development of sympathetic nervous system ................................................................ 3 1.1.4 Molecular biology ................................................................................................................. 5 1.1.4.1 DNA content .................................................................................................................. 5 1.1.4.2 Segmental chromosomal aberrations ............................................................................. 5 1.1.4.3 The MYCN proto-oncogene ............................................................................................ 5 1.1.5 Neuroblastoma and the hallmarks of cancer ......................................................................... 7 1.1.5.1 Sustained proliferative signalling .................................................................................... 7 1.1.5.2 Evasion of growth suppression ....................................................................................... 8 1.1.5.3 Evasion of apoptosis ......................................................................................................
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